This invention provides for novel unit doses of mifepristone to treat leiomyomata. Compared to unit dosages taught by the prior art, the claimed dosages are low and surprisingly effective. Furthermore, because higher dosages had undesired side effects, the prior art suggested that mifepristone was not suitable for long term clinical uses which are needed to treat leiomyomata. The advantages of this invention include a reduction of surgical morbidity, circumvent the need of a hysterectomy, and cost-effectiveness.
Leiomyomata are common pelvic fibroid tumors occurring in up to 20% of women over 30 years of age. Leiomyomata represent one of the most frequent indications of operative procedures in woman of reproductive age. Symptoms are reported in twenty to fifty percent of cases of leiomyomata. Symptoms include pelvic pain, excessive duration or amount of menstruation, infertility and pelvic masses.
Although the mechanisms of tumorigenesis are unknown, evidence suggests that leiomyomata are ovarian steroid dependent, Buttram, V. C., et al. (1981), Fertil. Steril., 36:433, incorporated herein by reference. Estrogen and growth hormone are thought to act synergistically to stimulate leiomyomata growth as the two are elevated during pregnancy when the growth of leiomyomata is rapid. That progesterone may play a role in Leiomyomata growth is suggested by the finding of increased mitotic count in leiomyomata obtained during the secretory phase than in proliferative phase of the menstrual cycle; Kawaguchi, et al. (1988) Am. J. Obstet. Gynecol., 160:637. Additionally, when the GnRH-agonist and a progesterone were co-administered, the expected regression of leiomyomata size seen with GnRH-agonist alone is not achieved, Friedman et al (1988) Fertil. Steril. 49:404. Wilson, E. R., et al. (1980) Obstet. Gynecol., 55:22 and Soules, M. R., et al. (1982) Am. J. Obstet. Gynecol., 143:6 have identified receptors for both estrogen (ER) and progesterone (PR) leiomyomata tissue.
The administration of gonadotropin releasing hormone (GnRH) agonists such as leuprolide, Schlaff, W. D., et al. (1989) Obstet. Gynecol., 74:857, Friedman, A. J., et al. (1987) Fertil. Steril., 48:560, Friedman, A. J., et al. (1991) Obstet. Gynecol., 77:720, goserelin, West, C. P., et al. (1987) Fertil. Steril., 48:45, and nafarelin, Andreyko, J. L., et al. (1988) Am. J. Obstet. Gynecol., 158:903, results in hypooestrogenism and causes reductions in the size of the fibroids. Unfortunately, GnRH agonist treatment cannot be continued indefinitely because of the associated vasomotor symptoms and adverse influence on bone mass. After cessation of treatment, the fibroids return to their original size within six months.
Mifepristone is a synthetic steroid with both antiprogesterone and antiglucocorticoid activities. The contragestational properties and clinical applications of mifepristone has been reviewed by Baulieu, E. E., (1989) Science 245:1351, and is incorporated herein by reference.
The antiglucocorticoid activity of mifepristone results in deleterious side effects glucocorticoid deprivation in the tissue and the pituitary gland resulting in an increase in serum ACTH and cortisol, as well as overt symptoms including complaints of anorexia, nausea, dizziness, weakness and somnolence.